Method of treating the syndrome of coronary heart disease risk factors in humans

ABSTRACT

The invention provides an improved method of treating a human suffering from one or more conditions included within the Coronary Heart Disease Risk Factor (CHDRF) syndrome. The method includes administering, by a pharmaceutically effective mode, a drug composition having an opioidergic agent including an opiate antagonist, opiate having μ-agonist activity or combination thereof, and an insulin secretagogue.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application is a continuation-in-part of and claims priorityto U.S. application Ser. No. 09/639,061 filed on Aug. 15, 2000.

BACKGROUND OF THE INVENTION

[0002] Coronary Heart Disease Risk Factors (CHDRFs) are major causes ofdeath in the industrialized world. CHD risk factors include Type 2Diabetes (and its precursor, Impaired Glucose Tolerance (IGT)),hyperlipidemia or dislipidemia, overweight, obesity and essentialhypertension, i.e., a form of hypertension that occurs without adiscoverable organic cause. The CHDRF syndrome may, therefore, bedefined as a group of interrelated disorders: Type 2 Diabetes, IGT,Dislipidemia, Overweight, Obesity and essential hypertension. It hasalso become apparent that Type 2 Diabetes, by itself, represents asyndrome of various, in part sequential, disease states which interactwith other components of the CHDRF syndrome. However, the exactinterrelationships between the disease states that make up thesesyndromes is not fully understood. A wide variety of chemical andphysical abnormalities associated with these syndromes exist. Theyinclude elevations in fasting blood glucose and gluconeogenesis in spiteof significant increases in fasting insulin and C-peptide concentrationsand increases in lipogenesis. Typically associated with lipogenesis areincreases in levels of fasting Free Fatty Acid (FFA), fastingtriglycerides (TG) and total cholesterol concentrations, increases inlevels of fasting Low Density Lipoprotein (LDL)-cholesterol, decreasesin levels of fasting High Density Lipoprotein (HDL)-cholesterol, anincreased LDL/HDL ratio, increases in body weight and increases insystolic and diastolic blood pressure.

[0003] Although these syndromes are interrelated and typically resultfrom derangements in nutrient metabolism, all the associated symptomsmay not be present in individual patients. Accordingly, in some patientslipid metabolism problems may predominate, while in others, carbohydratemetabolism problems may be predominant. While these factors, which lendone aspect of the syndrome to dominate over another, are not wellunderstood, it is clear that each portion of the syndrome, orcombinations of portions of the syndrome, represents risk factors incoronary heart disease.

[0004] Insulin Resistance/Beta-Cell Dysfunction/Type 2 Diabetes/CHDRFSyndrome

[0005] Common denominators in the etiology of the syndromes of Type 2Diabetes and the CHDRFs appear to be Insulin Resistance (IR) andBeta-Cell Dysfunction. IR is characterized as a state in which a normalamount of insulin produces a subnormal biological response incarbohydrate metabolism. This may be the case for subjects afflictedwith the non-insulin-dependent diabetes form of Type 2 Diabetes, inpre-diabetic subjects affected by Impaired Fasting Glucose (IFG) orImpaired Glucose Tolerance (IGT), and in overweight and obese subjects.These subjects require (and endogenously produce) higher than normallevels of insulin to compensate for their insulin resistance andBeta-Cell Dysfunction to normalize their blood glucose levels.Traditionally, IR has been expressed as the insulin/glucose ratio (I/G).More recently, several more complex models have been proposed to defineInsulin Resistance or the Insulin Sensitivity Index. Only recently haveother biological functions of insulin become the focus of more intensescientific interest, e.g. the role of insulin in endogenous lipogenesis.Although an interaction between insulin resistance and the CHDRFcomponents has been established, the cause and effect relationshipbetween insulin resistance, obesity, dislipidemia and IGT/Type 2Diabetes is still subject to debate. IR increases FFA and Triglyceride(TG) levels, which further contribute to IR, thereby creating a viciouscircle. Therapeutic modalities for lowering any one of the lipidfractions in dislipidemia have not proven capable of correcting theentire hyperlipidemic complex with a single therapeutic agent.

[0006] Compared to Type 1 juvenile) Diabetes, the Type 2 Diabetessyndrome, particularly its non-insulin-dependent mellitus (NIDDM) forms,is characterized by relatively inadequate endogenous insulinconcentrations. However, insulin concentrations in Type 2 diabetics may,in fact, be higher than in the normal population. A possible explanationfor this apparent discrepancy is that Type 2 diabetics, as well assubjects afflicted with IFG, IGT, Overweight or Obesity typicallyrequire more insulin to control their blood sugar levels. Temporaryincreases in certain diabetogenic mediators, such as glucagon, growthhormones and catecholamines may initially cause the requirement for moreinsulin. These mediators communicate their specific control functions asagonists to target tissue or cells through compatible cell boundreceptors. Continued, long term agonist load eventually leads to‘down-regulation’ of such receptors, i.e. the receptor response and/orsensitivity are decreased. Depending on the agonist involved, thismechanism can lead to tolerance or addiction. As a result, increasingdoses are required to achieve the same effect. Antagonists haveequivalent receptor specificity as their agonist counterparts, but donot convey any agonist-type control message. In contrast to agonists,prolonged exposure of such receptors to their specific antagonists canrestore receptor response or sensitivity, a process called receptor‘up-regulation’.

[0007] As long as any agonists load by mediators, such as hormones,neuro-transmitters or neuro-modulators prevails for infrequent, shortdurations, the respective receptors for such mediators can ‘up-regulate’between such temporary agonist loads. In other words, the receptors canresume their normal sensitivity between ‘receptor-ligand’ interactions.The early stage of IR may be characterized by temporary increases indiabetogenic mediators such as catecholamines, endogenous opiates,cortisol and/or glucagon.

[0008] Another early pathophysiologic indicator of the emergence of theCHDRF Syndrome is a condition called Beta-Cell Dysfunction.Non-diabetics experience a bi-phasic insulin response to an oral glucosechallenge, i.e. an acute, first phase governed by a rise in bloodglucose, and second, proportional phase characterized by a moresustained insulin release, following, in a quasi proportional manner,the post-prandial glucose excursion. Overweight and IGT subjects alreadyhave a significantly reduced first phase insulin release, whichvirtually disappears altogether once the subject becomes obese and ordiabetic. This condition exaggerates the Insulin Resistance relatedhyperglycemia and hyperinsulinemia and accelerates the severity of theCHDRF Syndrome.

[0009] A pharmacologic restoration of the vitally important first phaseinsulin release has, to this date, been an elusive scientificundertaking.

[0010] Resistance to the action of insulin in the control of glucose maynot carry over to the action of insulin on lipogenesis. Even though theindividual is resistant to the action of insulin in controlling glucose,the response of lipid metabolism to insulin may remain at the normallevel. As temporary agonist ‘loads’ become more frequent or sustained,the affected receptors will down-regulate. As a result, IR may become apermanent metabolic burden and, with additional diabetogenic factors,such as cortisol, may accelerate progressive increases in hepaticgluconeogenesis (GNG) and glucose production (GP). The IR dependentinsulin excess in the face of hyper-gluconeogenesis caused hyperglycemiathen becomes a blueprint for hyper- or dislipidemia, overweight andobesity. Gradually, the β-cells' secretory capacity to produce andsecrete insulin will diminish, resulting in a slow but steady rise infasting glucose levels until, eventually, such secretory capacity willbe exhausted, at which time the subject becomes ‘insulin dependent’,i.e. dependent on exogenous insulin injections.

[0011] Dislipidemia

[0012] Dislipidemia is characterized by any of the following, andcombinations thereof: elevated levels of total and LDL-cholesterol,elevated levels of TG, a high LDL/HDL ratio and elevated levels of FFAand low levels of HDL-cholesterol. Lipid metabolism is rather complex.While it is clear that dislipidemia is associated with the developmentof coronary heart disease, there is no clear understanding of thepathogenic causes and pathways leading up to the manifestation of thevarious lipid disorders. The relative roles of lipid ingestion versusendogenous lipogenesis in the etiology of lipid abnormalities have notbeen fully understood.

[0013] Overweight/Obesity

[0014] Obesity is a disease of major proportions and severe economicconsequences. No longer is obesity considered merely a physical orcosmetic inconvenience. Obesity is second only to cigarette smoking as apreventable cause of premature death, and its complications add inexcess of $100 billion to U.S. health care costs. Obesity can not betreated effectively by willpower alone, and currently availablepharmaceutical drugs are only marginally effective. Moreover, severalobesity drugs have recently been withdrawn from the market because oftheir risk of potentially fatal side-effects, e.g. pulmonaryhypertension or heart defects in connection with dexfenfluramine,fenfluramine or phentermine.

[0015] Six out of ten people (approximately 130 million) in the UnitedStates are overweight, close to 90 million are clinically obese and 22million are morbidly obese.

[0016] The definitions of obesity and overweight are somewhat arbitrary.The symptoms of overweight or obesity are characterized by excessivebody fat, i.e. the body contains a level of fat beyond that considerednormal. Body weight in relationship to height and build is used as asurrogate measure of obesity and overweight. Being 20% over the standardheight weight tables is considered obese. The body mass index (BMI) iscommonly used in defining normal weight. The BMI is calculated bydividing a subject weight in kilograms by the square of height in meters(kg/m2) or (lbs.×705/inches²). A BMI of 25 is considered normal, a BMIof 26-29 is considered overweight, a BMI of 30-40 is obese, and aBMI >40 is considered morbid. A therapeutic intervention is consideredeffective if it produces a weight reduction of >10%, or a reductionby >5% if ‘co-morbid’ factors are also improved, e.g. any of the bloodanalyte concentrations related to IGT, Type 2 Diabetes or dislipidemia.

[0017] Despite the recognized interaction between the various CHD riskfactors, the pharmaceutical modalities currently available to treat thesymptoms of Type 2 Diabetes generally have had no beneficial effect onhyper- or dislipidemia; in fact, some of the medicines widely used totreat Type 2 Diabetes, e.g. sulfonylureas, tend to increasehyperlipidemia and may, therefore, further contribute to overweight andobesity, thereby increasing the CHD risk. Conversely, medicinespresently available to treat various forms of hyper- or dislipidemiahave little or no impact on IFG, IGT, Type 2 Diabetes, overweight orobesity.

[0018] Moreover, no single pharmaceutical agent has been able to treatand correct the entire complex of hyper- or dislipidemia. Drugs such asclofibrate/gemfibrozil can lower TG levels, but have little or no effecton FFA levels, and no effect on total cholesterol levels. Other drugsmay shift the proportion of cholesterol found in the form of low andhigh density lipoprotein cholesterol. For example, certain drugs mayactually increase already elevated levels of low density lipoproteincholesterol. On the other hand, drugs like lovastatin lower the levelsof both total and low density lipoprotein cholesterol, while onlyslightly increasing the level of high density lipoprotein cholesterol.However, these drugs have no effect on FFA and little or no effect on TGlevels.

[0019] As a result, it is desirable to provide an improved method fortreating the syndrome of coronary heart disease risk factors. A newmethod for treating the early morning rise in hepatic gluconeogenesisand endogenous glucose production is also desired. In other words, animproved method of treatment is desired that lowers high glucose levelsresulting from rises in gluconeogenesis and glucose production, andimpaired insulin secretion in patients afflicted with CHD risk factorsin humans. A new method is also desired wherein the administration of adrug composition does not require a priming dose.

SUMMARY OF THE INVENTION

[0020] The present invention provides improved methods of treating ahuman suffering from one or more conditions included within the CoronaryHeart Disease Risk Factor (CHDRF) syndrome. The invention provides amethod including administering, by a pharmaceutically effective mode, adrug composition comprising an opioidergic agent (e.g. on opiateantagonist, an opiate having μ-agonist activity, or a combinationthereof) and an insulin secretagogue.

[0021] The invention further provides a method of treating a humansuffering from one or more conditions included within the Coronary HeartDisease Risk Factor (CHDRF) syndrome by administering, by apharmaceutically effective mode, a drug composition comprising an opiateantagonist and an insulin secretagogue.

[0022] The invention further provides a method of treating a humansuffering from one or more conditions included within the Coronary HeartDisease Risk Factor (CHDRF) syndrome by administering, by apharmaceutically effective mode, a drug composition comprising an opiateagonist and an insulin secretagogue.

[0023] Before embodiments of the invention are explained in detail, itis to be understood that the invention is not limited in its applicationto the details of the compositions and concentrations of components setforth in the following description. The invention is capable of otherembodiments and of being practiced or being carried out in various ways.Also, it is understood that the phraseology and terminology used hereinis for the purpose of description and should not be regarded aslimiting.

[0024] The patents, references and articles cited herein are herebyfully incorporated by reference.

BRIEF DESCRIPTION OF DRAWING

[0025]FIG. 1 is a graph showing the daily blood glucose profile of a72-year subject afflicted with Type 2 Diabetes and dislipidemia aftertreatments with an opioidergic drug composition in combination with aninsulin secretagogue. The blood glucose (BG) of the subject was measuredin mg/dL over several time intervals measured in hours (h).

DETAILED DESCRIPTION OF THE INVENTION

[0026] As used herein, the term “insulin secretagogue” is meant to referto any drug composition which stimulates, participates in thestimulation of, or potentiates, the secretion of insulin by thepancreatic Beta-Cells. Insulin secretagogues include insulinotropicagents and insulin secretion or release potentiators. Examples areprovided below.

[0027] As used herein, the terms “opioids,” “opioid agonists,” “opiateagonists,” “opiates having agonist activity” and “agonists” are meant torefer to opioid-like substances, natural or synthetic, that bind tocentrally and/or peripherally located opioid receptors to produce anagonist action.

[0028] As used herein, the terms “μ” “δ” and “κ” refer to the specifictypes of opiate receptors of cells such as brain, spinal cord and largeintestine.

[0029] As used herein, the terms “opiates having μ-agonist activity,”“opioids having μ-agonist activity” and “μ-agonists” are meant to referto opioid-like substances, natural or synthetic, that bind to the μopiate receptor to produce an agonist action.

[0030] As used herein, the terms “opioid antagonists,” “opiateantagonists,” “anti-opioids,” “antiopiates,” “opiates having antagonistactivity” and “antagonists” are meant to refer to opioid-like substancesthat bind to opioid receptors, but produce little or no agonistactivity.

[0031] As used herein, the terms “opiates having κ antagonist activity,”“opioids having κ antagonist activity” and “κ antagonists” are meant torefer to opioid-like substances that bind to the κ opiate receptor, butproduce little or no agonist activity.

[0032] As used herein, the terms “opioidergic agent” and “opioidergicdrug composition” are meant to refer to any of the above opioid-likesubstances as well as combinations thereof.

[0033] “Pharmaceutically effective modes” are meant to include, but notbe limited to, the application of a drug composition as a solution in aninnocuous pharmaceutically acceptable solvent, as an emulsion, as asuspension, as a dispersion in suitable carriers, as a patch or in theform of pills, or capsules with solid, liquid or gel carriers, and othersuch methods well-known in the art. The formulations of this inventionmay include pharmaceutically acceptable excipients such as stabilizers,anti-oxidants, binders, coloring agents, emulsifiers, and other suchexcipients well-known in the art. The drugs and drug compositionscomprising the agonists and antagonists described above and below, maybe administered in any pharmaceutically effective mode.

[0034] Opiate antagonists are molecular structures similar to opiatesbut do not have appreciable direct agonist activity. Antagonists havethe ability to reduce or prevent the receptor binding of opiateagonists, thus neutralizing their biologic effect. Anti-opioids, ornarcotic antagonists, are characterized by their ability to displacenarcotic agonists from the respective receptors. Since most narcoticspossess several agonist actions, e.g. μ, δ, and κ, anti-opioids maypossess antagonist capabilities for those (and other) receptors as well.In general, the antagonist activity, or effectiveness of anti-opioids isnot equal at the various receptor sites and may vary significantly,often times by more than an order of magnitude. For example, the μreceptor binding effectiveness for naltrexone may be 12 times higherthan its effectiveness to bind to a κ receptor, which may result in a12-fold increase of agonist displacement at the μ receptor over the κreceptor. Since the μ receptor is known to control (amongst others)euphoria, a suppression of this action 12-fold over any actioncontrolled by κ, e.g. for various metabolic functions can actuallyresult in disphoria, if the antiopioid dosage has to be increased toachieve the desired effect at the K site.

[0035] IC₅₀ is defined as the concentration of a compound at which 50%of the standard molecule is displaced from the target receptor. For eachreceptor there is a prototype ligand. To measure the IC₅₀ for a givenanti-opioid, one measures the concentration of the anti-opioid whichwill drive 50% of the prototype ligand from the target receptor. For theμ receptor the prototype ligand is DHM (dihydromorphine). For the δreceptor, the prototype ligand is DADLE (D-Ala+D-Leu-Enkephalin), andfor the K receptor, the prototype ligand is EKC (ethylketocyclazocine).

[0036] There are several types of opiate receptor sites and the opiateantagonists do not, generally, have an equipotent effect on all thedifferent receptor sites. In evaluating opiate antagonists for use inthe treatment of any or all of the CHDRF'S, their interaction with theμ, δ, and κ opiate receptors is most important. Opiate antagonists, suchas naloxone and naltrexone, which exert their greatest effect, byapproximately an order of magnitude, upon the μ receptors, may be usedto treat the CHDRFS, but may have undesirable CNS side effects due totheir dominant μ receptor antagonism versus the δ, and κ opioidreceptors, resulting in an enhanced κ agonist action. Opioid antagonistswhich have approximately equal effects on the μ, δ, and κ receptors aremore useful for the treatment of CHDRFS in humans. It has, further, beendiscovered that inhibition of the κ opiate receptor is important indetermining the effect of an anti opioid on the CHDRFS. It is,therefore, preferred that the anti-opioids have an effect upon the Kopiate receptor as strong as or stronger than effect upon the μ, and δopiate receptors. Since a strong inhibitory effect means that theanti-opioid is effective at low concentrations, it is desirable that theanti-opioids have a lower IC₅₀ for the κ opiate receptor than for the μ,and Δ opiate receptors.

[0037] The relationship between the IC₅₀ levels for the μ, δ, κ opiatereceptors may also be expressed in terms of a ratio. For example, if theIC₅₀ level for the μ, opiate receptor is within a factor of 3 of theIC₅₀ level for the δ opiate receptor then the ratio of the IC₅₀ levelfor the μ, opiate receptor to the IC₅₀ level for the δ opiate receptormay be expressed in the following manner: ⅓<(IC₅₀ δ/IC₅₀ μ)<3. Thepreferred anti-opioids or anti-opioid combinations for use in thetreatment of CHDRFC have a ratio of IC₅₀ for the κ opiate receptor tothe IC₅₀ for the μor δ receptors of 10 or less and most preferably 3 orless. These preferred compositions may be expressed as a ratio of IC₅₀values: {(IC₅₀ κ/IC₅₀ μ)<10}, and {(IC₅₀ κ/IC₅₀ δ)<10}; and the mostpreferred compositions have IC₅₀ values: {(IC₅₀ κ/IC₅₀ μ)<3}, and {(IC₅₀κ/IC₅₀ δ)<3}. antagonist such as nor-binaltorphimine is useful in thetreatment of any or all of the conditions which make up the CHDRFS. Itmay be used alone, or in combination with other anti-opioid drugs. Whenused as part of a combination drug, it serves to add further inhibitionof the κ opioid receptors to the properties of the combination.

[0038] Metformin hydrochloride is a non-sulfonylurea typeantihyperglycemic agent, which improves glucose tolerance in type 2diabetic subjects, primarily by decreasing hepatic gluconeogenesis andglucose production (Edelman, S. V.: Clinical Diabetes; 16,1:37-40). Themajor side effects are potential lactic acidosis, and the impact of therequired massive therapeutic doses on liver and kidney function.Metformin is, therefore, contraindicated for patients with hepatic andrenal insufficiency, which is aggravated by the fact that a typicaldaily dose ranges between 1,500 and 2,500 mg.

[0039] During the investigations into, and development of, non-addictivemorphine based analgesics, typically requiring a combination ofagonistic and antagonistic actions at various opiate receptor sites,i.e. μ, δand κ receptors, a variety of so-called ‘pure’ antagonists haveevolved as by-products, and some of these narcotic antagonists, oranti-opioids, have been shown to have potential in the treatment of avariety of disease conditions.

[0040] U.S. Pat. No. 4,272,540 discloses various 14-methoxy substituted3-hydroxy or 3-methoxy-6-one morphinans, which are variously useful asanalgesics, narcotic antagonists, and mixed analgesics and narcoticantagonists.

[0041] U.S. Pat. No. 4,451,470 discloses 14-fluoromorphinans which areuseful as analgesic, narcotic antagonists and/or anorexigenic agents.

[0042] U.S. Pat. No. 4,478,840 discloses17-cycloalkylmethyl-4,-5α-epoxymorphinan-3,14-diol compounds useful forsuppression of appetite in mammals.

[0043] U.S. Pat. No. 4,619,936 discloses pharmaceutical compositionscontaining(5α,6α)7,8-didehydro-4,5-epoxy-17-(2-propanyl)-morphinano-3,6-diol forthe purpose of appetite reduction.

[0044] U.S. Pat. No. 4,882,335 discloses a method useful as an adjunctin the treatment of alcoholism. The method involves having the patientdrink alcoholic beverages, while an opiate antagonist blocks thepositive reinforcement effects of ethanol in the brain.

[0045] U.S. Pat. No. 5,086,058 discloses a method for treatingalcoholism. The method involves having the patient drink alcoholicbeverages while nalmefene, an opiate antagonist, blocks the positivereinforcement effects of ethanol in the brain.

[0046] In order to address the dramatic increases in diabetes, obesityand other CHDRFs, and their effects on patient morbidity/mortality andnational health care expenditures, the focus of pharmaceutical researchis shifting from post symptomatic stabilization to prevention andintervention. The pathophysiology of the syndrome CHDRFs is aprogressive process with changing conditions, as physiologic controlfunctions become strained, exhausted and, eventually, supplemented orreplaced by other compensatory mechanisms. Therefore, the differentstages in this progression necessitate different interventive measurestailored to retain or restore those functions still viable.

[0047] U.S. Pat. No. 5,727,570 discloses a method of treatment of humanssuffering from hyperlipidemia by administering a drug compositionselected from a group consisting of opiate antagonists and drugs whichsubstantially equally reduce the amount of catecholamines bound tocatecholamine binding sites. In a model case study, conducted with apure anti-opioid, this method was applied during the pre-diabetic stageof IFG combined with IR, and resulted in significant improvements in allcarbohydrate and lipid control functions, restoring all relevant BloodAnalyte Concentrations (BAC) to normal physiologic levels, with areduction of FBG to 95 mg/dL.

[0048] U.S. Pat. No. 5,878,750 discloses a method of treating humanssuffering from the Coronary Heart Disease Risk Factor syndrome byadministering a drug composition selected from the group of opiateantagonists or anti-opioids and drugs which substantially equally reducethe amounts of catecholamines bound to all catecholamine binding sites.A model case study involved the administration of a pure opioidantagonist to an overweight subject with early stage Type 2 Diabetes anddislipidemia, having a fasting blood glucose level (FBG) of 138 mg/dL,which is exceeding the criteria for IFB and IGT. Although allcarbohydrate and lipid metabolism related BACs, as well as overweightand hypertension, showed significant improvements, all were restoredback to normal, with the exception of FBG which, despite its 13%improvement, only dropped from 138 mg/dL to 120 mg/dL, still within theIGT range.

[0049] U.S. Pat. No. 6,026,817 discloses a method of treatment of humanssuffering from the syndrome of Coronary Heart Disease Risk Factors whichcomprises the steps of 1) administering a priming dose of a drugcomposition selected from the group consisting of opioid antagonists and2) administering a maintenance dose of said drug. It also discloses amethod of combining said dosing sequence with a method of improving thebalance between or equalizing the IC-50 values of an anti-opioidcomposition for its respective target receptors, by adding small amountsof one or more drugs with opioid agonist activity whereby the agonistcompetes with the antagonist for the particular receptor, anddiminishes, but does not totally remove any of the respective antagonistproperties of the anti-opioid composition.

[0050] The present invention provides an improved method of treating theSyndrome of CHD risk factors, by the administration of insulinsecretagogues in combination with an opioidergic drug composition. Thesyndrome of CHD risk factors includes the various disease states of Type2 Diabetes, as well as hyper- or dislipidemia, overweight, obesityand/or essential hypertension. The disease states of the Type 2 Diabetessyndrome progress through insulin resistance (IR) and Beta-Celldysfunction, impaired fasting glucose (IFG), excessive hepaticgluconeogenesis (GNG) and glucose production (GP), and impaired glucosetolerance (IGT) to the clinical form of Type 2 Diabetes. The improvedmethod provides a treatment for any number of individual conditionswithin the syndromes of CHDRF and Type 2 Diabetes. This invention alsoprovides a method of treating the early morning increase ingluconeogenesis and increased glucose production which, in the presenceof relatively impaired insulin secretion, results in elevated fastingglucose levels. This invention further provides a method to restore thephysiologic acute, first phase insulin release.

[0051] Non-glucose dependent insulin secretagogues, such assulphonylureas, stimulate insulin secretion regardless of the bloodglucose level and are, therefore, prone to produce potentiallydeleterious hypoglycemia, particularly so, because such insulinsecretagogues primarily increase the second phase insulin release withno improvement in first phase insulin secretion.

[0052] This invention of administering, by a pharmaceutically effectivemode, opioidergic drug compositions in combination with non-glucosedependent insulin secretagogues, such as sulphonylureas, can confer amore glucose dependent, bi-phasic insulin release pattern on suchsecretagogues, and significantly reduce the likelihood of producinghypoglycemia.

[0053] Another aspect of this invention is to provide an improved firstpass insulinization of the liver, resulting in a restoration of enzymefunctions involved in hepatic fuel processing, including carbohydrateoxidation and storage.

[0054] Drugs which are useful in the methods of the present invention,i.e. improved methods for treating humans suffering from CHD riskfactors, include opioid drug compositions of non-selective or selectiveopioid antagonists, with or without the supplementation of centrally orperipherally acting μ-agonist activity, and in combination with insulinsecretagogues, including insulinotropic agents and/or insulin secretionor release potentiators. Insulin secretagogues include, but are notlimited to, sulphonylureas, such as tolbutamide, chlorpropamide,glimepiride, glipizide, and glyburide, (all listed in Merck Index,12^(th) Edition, 1996), repaglinide, (Raskin P et.al.: Diabetes Care23[7]:979-83), meglitinides, morphilinoguanide and pramlintide (Evans AJ and Kreutz A J: Drugs RD 2[2]:75-94), acetylcholine (Tae Niwa et. al.:Diabetes 47: 1699-1706), muscarinic agonists, e.g. carbachol (Hiriart Mand Ramirez-Medeles M C: Mol Cell Endocrinol 93[1]: 63-9), bethanechol(Physicians Desk Reference [PDR]), beta-L-glucose pentaacetate,(Malaisse W J et.al.: American Journal of Physiology 276[6/1]:E993-E1006), chiro-inositol (Larner J. et.al. U.S. Pat. No. 5,428,066),myo-inositol (Szkudelski T and Kandulska K.: Arch. Physiol. Biochem.107[4] :334-7), GIP (Kindmark H et.al.:J Clin Endocrinol Metab86[5]:2015-9), GLP-1 and Extendin-4 (Parkes DG et.al.: Metabolism50[5]:583-9).

[0055] It is preferred to administer the μ-agonist compositionconcurrently with the opioid antagonist drug compositions and selectcombinations having compatible biologic half-lives in order tofacilitate the matching of their respective pharmacodynamics.

[0056] Bi-directional effects of opioids are known to exist, inparticular between μ and κ agonists, such as μ-agonists producingeuphoria and κ agonists producing the opposite, namely disphoria.Conversely, μ antagonists can antagonize euphoria and enhance the effectof the κ agonist, while the κ antagonist can produce or enhanceeuphoria. Examples of this phenomenon also include the opposing effectsof μ and κ opiates in motivational processes (Herz A.: NIDA Res Monogr90:17-26), or in opioid reward mechanisms (Herz A.: Can J PhysiolPharmacol 76,3:252-8), and other μ-opposing actions of the κ-opioidreceptor (Pan Z. Z.: Trends Pharmacol Sci; 19,3: 94-8).

[0057] Opioids having selective or predominant κ-antagonist activityinclude, but are not limited to nalmefene, naltrexone,nor-binaltorphine, (Portoghese, P. S., Lipkowski, A. W., Takemori, A.E.; Life Sciences 40: 1287-92); guanidylated naltrindole (GNTI), (JonesR. M., Hjorth, A. S., Schwartz, T. W., and Portoghese, P. S.; Journal ofMedicinal Chemistry 41,25: 4911-4),(−)-(1R,5R,9R)-5,9-diethyl-2-(3-furylmethyl)-2-hydroxy-6,7-benzomorphan(MR 2266) (Merz, H., Langbein, A., Stockhaus, K., Walther, G., & Wick,H.; Advances in biochemical psychopharmacology, Vol 8: 91-107), atriethylenedioxy derivative of naltrexamine (TENA), (Portoghese, P. S.,Takemori, A. E.; Life Sciences 36: 801-5) and buprenorphine.

[0058] Opioids having selective or predominant U-agonist activityinclude, but are not limited to, dihydromorphine, morphine,hydromorphone, methadone, fentanyl, sufentanyl, buprenorphine,demorphine, codeine, ethylmorphine, etonitazene, hydrocodone,levorphanol, norcodeine, normorphine, loperamide,{D-Ala²-N-Me-Phe⁴-Gly⁵-ol)-Enkephalin} (DAMGO) and oxycodone. Mostopioids pass the Blood Brain Barrier (BBB) and are, therefore both,centrally and peripherally active, i.e. they can act upon CNS sites aswell as peripheral sites, such as the gut and hormone producing glands,including the endocrine pancreas and the adrenal medulla. Some opioids,e.g. loperamide, do not pass the BBB and are, therefore, onlyperipherally active with little or no CNS effect. Since drug addictiongenerally requires a central effect, peripherally acting opioid agonistsare typically not addictive and generally not ‘scheduled’ as narcotics.

[0059] Buprenorphine is a mixed agonist-antagonist having high affinityat the μopiate receptor with partial agonist activity, and at the κreceptor with antagonist activity. Because of its κ receptor antagonistactivity and low partial μ activity it will produce minimal and perhapsclinically insignificant physical dependence. Bupreprohine has been usedas an effective analgesic for the treatment of moderate to severe painand of opioid dependence. (Lewis J. W.: Drug and Alcohol Dependence;14:363-372). Elevations in cortisol and glucose, caused by surgicalstress, have been observed to decline following the administration ofbuprenorphine to treat analgesia during and following total hipreplacement (McQuay H. J. et. al.: Br J Anaesth; 52:1013-19).

[0060] Loperamide is a synthetic opioid used for the treatment ofdiarrhea, which is more effective and safe than other opioid drugs inthe treatment of diarrhea of various causes (Ruppin H: Acta PhysiolScand; 127,3:275-9) Loperamide is a ‘non-scheduled’ opioid withμ-agonist activity as opposed to most other opioid agonists which arelisted as ‘controlled substances.’ Loperamide is reported to raise bloodglucose concentrations at dose levels required for the acute treatmentof diarrhea (Caldara R. et. al.: Eur J Clin Pharmacol; 21,3:185-8), andhas been used in the “Loperamide test”: a simple and highly specificscreening test for hypercortisolism in children and adolescents” (BuziF. et. al.: Acta Paediatr; 86,11: 1177-80).

[0061] The invention results in an improved method of treating coronarydisease risk factors and an improvement toward normal values of fastingblood glucose, C-peptide, fasting total cholesterol, fastingLDL-cholesterol, fasting HDL-cholesterol, LDL/HDL ratio, fasting TG,fasting FFA, body weight, systolic blood pressure and/or diastolic bloodpressure.

EXAMPLE

[0062] The example is being described for purely illustrative purposes,and is in no way meant to limit the scope of the invention.

[0063] The daily blood glucose profile of a 72 year old subject withType 2 Diabetes and dislipidemia was monitored following the earlymorning oral administration of 0.15 mg Hydrocodone, a centrally actingμ-agonist in combination with sulfonylurea type insulin secretagogue.The glucose profile of the subject was monitored on the second day afterthe treatment had been initiated. Sufficient time was allowed after theearlier treatment to eliminate any carry-over effect. Treatment 1 (-O-)no drug treatment. Breakfast: 08:40-09:00; lunch: 12:25-12:50; dinner:18:40-19:00 time [h] 08:10 10:00 12:20 14:00 18:30 20:00 BG [mg/dL] 132156 104 150 98 117

[0064] Treatment 2 (-▪-) 0.15 Hydrocodone, a centrally acting μ-agonistin combination with 1.0 mg Glipizide, administered 2 hours beforebreakfast Breakfast: 09:00-09:15; lunch: 12:10-12:30; dinner:19:20-19:50 Time 08:45 09:00 09:15 09:50 10:35 11:05 12:10 12:30 13:0014:05 19:25 19:50 20:25 20:55 [h] BG 103 102 102 108 116 104 109 100 10894 92 88 105 89 [mg/dL]

[0065]FIG. 1 and the supporting data demonstrate that post prandialpeaks in glucose concentration have been virtually normalized with theadministration of 0.15 mg of hydrocodone in combination with 1.0 mg ofthe sulfonylurea type insulin secretagogue glipizide. The administrationof the μ-agonist in combination with the insulin secretagogue alsoresults in very significant increases in first phase insulin release, ascan be derived from the pronounced decreases of blood glucoseconcentrations throughout the intake of the meals, and from the reducedduration and excursions of the post-prandial peaks, compared to placebo.

[0066] Type 2 Diabetes, IGT, overweight and obesity are associated withdefective or lacking first phase insulin release, as is Type 1 Diabetes.In contrast to Type 1 Diabetes, all these afflictions, except late stageType 2 Diabetes, retain second, proportional phase insulin secretorycapacity. The restoration of hepatic carbohydrate oxidation and storagein Type 1 Diabetics requires appropriately controlled exogenous insulininfusions.

[0067] According to the present invention, such restoration of hepaticcarbohydrate oxidation storage in subjects afflicted with the CHD riskfactors is achieved by administration of opioidergic drug compositionsin combination with insulin secretagogues. The opioidergic drugcompositions useable in the present invention may be single substancesor may also be any combination of opioid agonists, antagonists or mixedagonist/antagonists as long as their respective pharmacodynamics are, orhave been rendered, compatible, in order to avoid significant variationsin their respective, and combined, biologic effectiveness throughouttheir decline in biologic action.

[0068] The effective dose of the μ-agonist loperamide is, typically,less than 0.5 mg per day, or smaller by more than an order of magnitudethan the typical dose required for the treatment of diarrhea, and theeffective dose for hydrocodone is, typically, less than 1 mg. Theeffective dose for these and other μ-agonists, or single- ormulti-molecular mixed μ-agonist/κ-antagonist compositions as well as theinsulin secretagogues may vary depending upon factors such as the(patho-)physiology of the subject being treated, receptor binding, theabsorption rate, bio-availability, excretion rate and the rate ofmetabolism of the drug. The pharmacokinetic compatibility between theopioidergic agent and the insulin secretagogue is less critical, but thepreferred biologic half life of the insulin secretagogue is less than 4hours. The preferred method of administration is such that the peakplasma concentration of the drug combination occurs before or duringbreakfast.

[0069] The effective dose for the supplementary insulin secretagoguesis, typically, equal or less than the dose for such agents used inmonotherapy.

[0070] The examples are being described for purely illustrativepurposes, and are in no way meant to limit the scope of the invention.

I claim:
 1. A method of treating a human suffering from one or moreconditions included within Coronary Heart Disease Risk Factor (CHDRF)syndrome, the method comprising administering, by a pharmaceuticallyeffective mode, a drug composition comprising: an opioidergic agent; andan insulin secretagogue.
 2. The method of claim 1, wherein theopioidergic agent is an opiate antagonist, an opiate having μ-agonistactivity or a combination thereof.
 3. The method of claim 2, wherein theopiate antagonist comprises a single molecular entity.
 4. The method ofclaim 2, wherein the opiate antagonist comprises a combination ofmolecular entities.
 5. The method of claim 2, wherein the opiate havingμ-agonist activity comprises a single molecular entity.
 6. The method ofclaim 2, wherein the opiate having μ-agonist activity comprises acombination of molecular entities.
 7. The method of claim 2, wherein thedrug composition comprises a peripherally acting μ-agonist.
 8. Themethod of claim 7, wherein the drug composition comprises loperamide. 9.The method of claim 2, wherein the drug composition comprises acentrally acting μ-agonist.
 10. The method of claim 2, wherein the drugcomposition further comprises an opiate having mixed μ-agonist and κantagonist activity.
 11. The method of claim 10, wherein the opiatehaving mixed μ-agonist and κ antagonist activity is buprenorphine. 12.The method of claim 2 wherein the opioidergic agent includes at leastone of the following: i) dihydromorphine; ii) morphine; iii)hydromorphone; iv) methadone; v) fentanyl; vi) sufentanyl; vii)buprenorphine; viii) demorphine; ix) codeine; x) ethylmorphine; xi)etonitazene; xii) hydrocodone; xiii) levorphanol; xiv) norcodeine; xv)normophine; xvi) (D-Ala²-N-Me-Phe⁴-Gly³-ol)-Enkephalin (DAMGO); andxvii) oxycodone.
 13. The method of claim 2, wherein the opioidergicagent includes at least one of the following: i) nalmefene; ii)naltrexone; iii) nor-binaltorphine; iv)(−)-(1R,5R,9R)-5,9-diethyl-2-(3-furylmethyl)-2-hydroxy-6,7-benzomorphan(MR2266); v) a triethylenedioxy derivative of B-naltrexamine (TENA); andvi) guanidylated naltrindole (GNTI).
 14. The method of claim 2, whereinthe condition included within the CHDRF Syndrome is Insulin Resistance(IR).
 15. The method of claim 2, wherein the condition included withinthe CHDRF Syndrome is Beta-Cell Dysfunction.
 16. The method of claim 2,wherein the condition included within the CHDRF Syndrome is ImpairedGlucose Tolerance (IGT).
 17. The method of claim 2, wherein thecondition included within the CHDRF Syndrome is Type 2 Diabetes.
 18. Themethod of claim 2, wherein the condition included within the CHDRFsyndrome is overweight.
 19. The method of claim 2, wherein the conditionincluded within the CHDRF syndrome is obesity.
 20. The method of claim2, wherein the condition included within the CHDRF syndrome isdyslipidemia.
 21. The method of claim 1, wherein the insulinsecretagogue includes at least one of the following: i. sulphonylureas;ii. tolbutamide; iii. chlorpropamide; iv. glimepiride; v. glipizide; vi.glyburide; vii. meglitinides; viii. repaglinide; ix. pramlintide; x.morphilinoguanide; xi. acetylcholine; xii. muscarinic agonists; xiii.carbachol; xiv. bethanechol; xv. beta-L-glucose pentaacetate; xvi.chiro-inositol; xvii. myo-inositol; xviii. GIP; xix. GLP-1; and xx.Extendin-4.
 22. The method of claims 1, wherein the insulin secretagogueis a non-glucose dependent insulin secretagogue, the method producinginsulin release patterns capable of attaining glucose dependent,bi-phasic release characteristics with reduced likelihood of producinghypoglycemia.
 23. The method of claim 22, wherein the insulinsecretagogue is sulphonylurea.
 24. A method of treating a humansuffering from one or more conditions included within Coronary HeartDisease Risk Factor (CHDRF) syndrome, the method comprisingadministering, by a pharmaceutically effective mode, a drug compositioncomprising: an opiate antagonist; and an insulin secretagogue.
 25. Themethod of claim 24, wherein the opiate antagonist comprises a singlemolecular entity.
 26. The method of claim 24, wherein the opiateantagonist comprises a combination of molecular entities.
 27. The methodof claim 24, wherein the opiate antagonist includes at least one of thefollowing: i) nalmefene ii) naltrexone; iii) nor-binaltorphine; iv)(−)-(1R,5R,9R)-5,9-diethyl-2-(3-furylmethyl)-2-hydroxy-6,7-benzomorphan(MR2266); v) a triethylenedioxy derivative of B-naltrexamine (TENA); andvi) guanidylated naltrindole (GNTI).
 28. The method of claim 24, whereinthe condition included within the CHDRF Syndrome is Insulin Resistance.29. The method of claim 24, wherein the condition included within theCHDRF Syndrome is Beta-Cell Dysfunction.
 30. The method of claim 24,wherein the condition included within the CHDRF syndrome is ImpairedGlucose Tolerance (IGT).
 31. The method of claim 24, wherein thecondition included within the CHDRF syndrome is Type 2 Diabetes.
 32. Themethod of claim 24, wherein the condition included within the CHDRFsyndrome is overweight.
 33. The method of claim 24, wherein thecondition included within the CHDRF syndrome is obesity.
 34. The methodof claim 24, wherein the condition included within the CHDRF syndrome isdislipidemia.
 35. The method of claim 24 wherein the opiate antagonisthas IC₅₀ levels for the μ, δ, and κ opiate receptors, the IC₅₀ levelsbeing {(IC₅₀ κ/IC₅₀ μ)<3} and {(IC₅₀ κ/IC₅₀ δ)<3}.
 36. The method ofclaim 24, wherein the insulin secretagogue includes at least one of thefollowing: i. sulphonylureas; ii. tolbutamide; iii. chlorpropamide; iv.glimepiride; v. glipizide; vi. glyburide; vii. meglitinides; viii.repaglinide; ix. pramlintide; x. morphilinoguanide; xi. acetylcholine;xii. muscarinic agonists; xiii. carbachol; xiv. bethanechol; xv.beta-L-glucose pentaacetate; xvi. chiro-inositol; xvii. myo-inositol;xviii. GIP; xix. GLP-1; and xx. Extendin-4.
 37. The method of claims 24,wherein the insulin secretagogue is a non-glucose dependent insulinsecretagogue, the method producing insulin release patterns capable ofattaining glucose dependent, bi-phasic release characteristics withreduced likelihood of producing hypoglycemia.
 38. The method of claim37, wherein the insulin secretagogue is sulphonylurea.
 39. A method oftreating a human suffering from one or more conditions included withinthe Coronary Heart Disease Risk Factor (CHDRF) syndrome, the methodcomprising administering, by a pharmaceutically effective mode, a drugcomposition comprising: an opiate agonist; and an insulin secretagogue.40. The method of claim 39, wherein the opiate agonist comprises asingle molecular entity.
 41. The method of claim 39, wherein the opiateagonist comprises a combination of molecular entities.
 42. The method ofclaim 39, wherein the opiate agonist is a peripherally acting μ-agonist.43. The method of claim 42, wherein the opiate agonist is loperamide.44. The method of claim 39, wherein the opiate agonist is a centrallyacting μ agonist.
 45. The method of claim 39, wherein the opiate agonistincludes at least one of the following: i) dihydromorphine; ii)morphine; iii) hydromorphone; iv) methadone; v) fentanyl; vi)sufentanyl; vii) demorphine; viii) codeine; ix) ethylmorphine; x)etonitazene; xi) hydrocodone; xii) levorphanol; xiii) norcodeine; xiv)normophine; xv) (D-Ala²-N-Me-Phe⁴-Gly³-ol)-Enkephalin (DAMGO); and xvi)oxycodone.
 46. The method of claim 39, wherein the condition includedwithin the CHDRF Syndrome is Insulin Resistance.
 47. The method of claim39, wherein the condition included within the CHDRF Syndrome isBeta-Cell Dysfunction.
 48. The method of claim 39, wherein the conditionincluded within the CHDRF syndrome is Impaired Glucose Tolerance (IGT).49. The method of claim 39, wherein the condition included within theCHDRF syndrome is Type 2 Diabetes.
 50. The method of claim 39, whereinthe condition included within the CHDRF syndrome is overweight.
 51. Themethod of claim 39, wherein the condition included within the CHDRFsyndrome is obesity.
 52. The method of claim 39, wherein the conditionincluded within the CHDRF syndrome is dislipidemia.
 53. The method ofclaim 39, wherein the insulin secretagogue includes at least one of thefollowing: i. sulphonylureas; ii. tolbutamide; iii. chlorpropamide; iv.glimepiride; v. glipizide; vi. glyburide; vii. meglitinides; viii.repaglinide; ix. pramlintide; x. morphilinoguanide; xi. acetylcholine;xii. muscarinic agonists; xiii. carbachol; xiv. bethanechol; xv.beta-L-glucose pentaacetate; xvi. chiro-inositol; xvii. myo-inositol;xviii. GIP; xix. GLP-1; and xx. Extendin-4.
 54. The method of claims 39,wherein the insulin secretagogue is a non-glucose dependent insulinsecretagogue, the method producing insulin release patterns capable ofattaining glucose dependent, bi-phasic release characteristics withreduced likelihood of producing hypoglycemia.
 55. The method of claim39, wherein the insulin secretagogue is sulphonylurea.